1. Field of the Invention
The present invention relates to amidinophenol derivatives, processes for the preparation thereof and the use thereof as leukotriene B.sub.4 (LTB.sub.4)antagonists, phospholipase A.sub.2 inhibitors, and trypsin inhibitors.
More particularly, it relates to LTB.sub.4 antagonists containing an amidinophenol derivative of the formula (IA): ##STR3##
(wherein various symbols are the same meanings as hereafter described), as the active ingredient; to
amidinophenol derivatives of the formula (IB): ##STR4##
(wherein various symbols are the same meanings as hereafter described) and processes for the preparation thereof; and to LTB.sub.4 antagonists, phospholipaseA.sub.2 inhibitors and trypsin inhibitors containing a compound of formula (IB) as the active ingredient.
2. Description of Related Art
The metabolic pathways by which various compounds are biosynthesized, in vivo, from arachidonic acid as a common starting material are called the arachidonic acid cascade.
Lipoxygenase, for example, 5-lipoxygenase, 12-lipoxygenase or 15-lipoxygenase, respectively, acts on arachidonic acid to produce 5-HPETE, 12-HPETE or 15-HPETE from arachidonic acid.
The above mentioned HPETEs are converted into 5-HETE, 12-HETE or 15-HETE, by converting a peroxy group into a hydroxy group by the action of peroxidase, and 5-HPETE is also converted into LTA.sub.4.
LTA.sub.4 is converted into LTB.sub.4 or LTC.sub.4 by enzymatic reaction (see Biochem. Biophys. Res. Commun., 91, 1266 (1979), Prostaglandins, 19(5), 645).
Recently a number of properties of LTB.sub.4 have been revealed.
It is understood that LTB.sub.4 has strong chemotactic and adhesive activity and degranulation activity on leukocytes (see Nature, 286, 264 (1980), Proc. Nat. Acad. Sci. USA, 78, 3887 (1981)).
LTB.sub.4 also has strong calcium ionophore action, and attacks various cells, and it is considered to accelerate release of metabolites of arachidonic acid from these cells (see J. Biol. Chem, 257, 4746 (1982)).
High levels of LTB.sub.4 have also been found at sites of various inflammations, for example, rheumatism, spondyl arthritis, gout, psoriasis, ulcerative colitis and respiratory tract diseases, thereby demonstrating that LTB.sub.4 is closely associated with various inflammations (see J. Clin. Invest., 66, 1166 (1980); Lancet II 1122-1123 (1982); J. Invest. Dermatol., 82, 477-479 (1984); Gastroenterology 86, 453-460 (1984)).
It is therefore considered that LTB.sub.4 antagonists are useful as anti-inflammatory agents or anti-allergic agents.
It is known that LTB.sub.4 antagonists are also useful for the treatment of rheumatoid arthritis, inflammatory bowel diseases, psoriasis, nonsteroidal anti-inflammatory agent-induced stomach diseases, adult respiratory distress syndrome, cardiac infarction, allergic rhinitis, hemodialysis-induced neutropenia, anaphase asthma (see the specification of the Japanese Patent Kokai No. 5-239008).
Phospholipase A.sub.2 (PLA.sub.2) is an enzyme which acts on phospholipids existing in cell membranes. It hydrolyzes an ester bond at the second position of the phospholipids. There are two known kinds of PLA.sub.2, membrane-associated PLA.sub.2 and pancreatic PLA.sub.2.
Membrane-associated PLA.sub.2 acts on phospholipids to release arachidonic acid (AA) from the phospholipids. The AA is converted into prostaglandins, thromboxanes and leukotrienes, which are physiologically active substances inducing various inflammatory diseases and allergic diseases.
On the other hand, pancreatic PLA.sub.2 degrades phospholipids and destroys cell membranes, thereby producing lysolecithin having strong cytotoxicity. Recently, much importance has been attached to pancreatitis, severity in pancreatitis and multiple organ failure induced by this destructive activity on cell membranes.
It is also reported that membrane-associated PLA.sub.2 is also concerned with these diseases.
Accordingly, the inhibition of PLA.sub.2 leads to the suppression of the release of AA, a precursor of various physiologically active substances, and therefore, it is considered to be useful for the prevention and/or the treatment of various inflammatory and allergic diseases. Furthermore, it is considered to be useful for the prevention and/or the treatment of pancreatitis, severity in pancreatitis and multiple organ failure due to the inhibition of the destructive activity on cell membranes.
It is also known that the inhibition of various proteases such as trypsin, plasmin, thrombin, kallilrein, especially trypsin is useful for the prevention and/or the treatment of disseminated intravascular coagulation, pancreatitis, severity in pancreatitis and multiple organ failure.
In the specifications of EP-A-588655 and 656349, it is disclosed that cetain amidinophenol compounds of the formula (IA) depicted hereinafter have an inhibitory activity on PLA.sub.2 and an inhibitory activity on trypsin and are useful for the prevention and/or the treatment of various inflammatory or allergic diseases, disseminated intravascular coagulation, pancreatitis, severity in pancreatitis and multiple organ failure.
Several amidinophenol derivatives are known to be LTB.sub.4 antagonists. They are disclosed in WO 94/11341, the specification of Japanese Patent Kokai No. 5-239008 and EP-518819. In these applications, it is disclosed that amidinophenyloxy (thio) alkyloxy (thio) benzamide is useful as an LTB.sub.4 antagonist.
For example, it is described in the specification of EP-518819 that compounds of the formula (A): ##STR5##
wherein
R.sup.1a is amino which is mono- or disubstituted by a substituent selected from an aliphatic hydrocarbon radical, an araliphatic hydrocarbon radical, an aromatic radical, and a cycloaliphatic hydrocarbon radical or is amino which is disubstituted by a divalent aliphatic hydrocarbon radical; PA1 R.sup.2a is hydrogen, halogen, trifluoromethyl, an aliphatic hydrocarbon radical, or is hydroxy which is etherified by an aliphatic alcohol, araliphatic alcohol, or aromatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid; PA1 R.sup.3a is hydrogen or an acyl radical which is derived from an organic carbonic acid, an organic carboxylic acid, a sulfonic acid, or a carbamic acid; X.sub.1a and X.sub.3a, independently of one another, are oxygen (--O--) or sulphur (--S--); PA1 X.sub.2a is a divalent aliphatic hydrocarbon radical which may be interrupted by an aromatic radical; PA1 wherein the phenyl rings of formula (A) may be, independently of one another, further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid; PA1 wherein aryl moieties in the above definitions may be, independently of one another, further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid; and PA1 wherein a cycloaliphatic hydrocarbon radical may be substituted by an aliphatic radical; PA1 R.sup.0 is hydrogen, C1-4 alkyl, or C1-4 alkoxy, PA1 T is NH or oxygen, PA1 E is a single bond, or a group of the formula: ##STR9## PA1 R is a group of the formula: ##STR10## PA1 R.sup.50, R.sup.60 and R.sup.70 each independently, is, PA1 T is oxygen, the group: ##STR12## PA1 is the formula (i) as hereinbefore described, PA1 E is a single bond, PA1 A.sub.0 is a single bond, C1-4 alkylene or vinylene which is optionally substituted by one or two C1-4 alkyl, and PA1 R is the formula (i) as described above, then at least one group in R.sup.50, R.sup.60 and R.sup.70 is PA1 T is oxygen, the group ##STR13## PA1 is the formula (i) as hereinbefore defined, PA1 E is a single bond, PA1 A.sub.0 is a single bond, C1-4 alkylene or vinylene optionally substituted by one or two C1-4 alkyl, and PA1 R is the formula (ii) as defined above, PA1 then R.sup.50, R.sup.60 and R.sup.70 do not represent hydrogen; PA1 R.sup.1 and R.sup.2 each independently, is: PA1 A is PA1 R.sup.3 is PA1 wherein R.sup.11a is PA1 R.sup.9 is PA1 the group: ##STR16## PA1 is a 4-7 membered mono hetero ring contain one or two nitrogen; PA1 R.sup.10 is PA1 with the proviso that: PA1 (1) using an acid halide, PA1 (2) using a mixed acid anhydride or PA1 (3) using a condensing agent. PA1 (1) the method using an acid halide may be carried out, for example, by reacting a carboxylic acid with an acid halide (e. g., oxalyl chloride, thionyl chloride etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) or without a solvent at from -20.degree. C. to the reflux temperature of the solvent, and then by reacting the acid halide obtained with a corresponding alcohol in the presence of a tertiary amine (e. g., pyridine, triethylamine, diethylaniline, diethylaminopyridine etc.) in an inert organic solvent (e. g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) at a temperature of from 0.degree. C. to 40.degree. C.; PA1 (2) the method using a mixed acid anhydride may be carried out, for example, by reacting a carboxylic acid and an acid halide (e. g., pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acid derivative (e. g., ethyl chloroformate, isobutyl chloroformate etc.) in the presence of a tertiary amine (e. g., pyridine, triethyamine, dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent (e. g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) or without a solvent at a temperature of from 0.degree. C. to 40.degree. C., and then by reacting the mixture of acid anhydride obtained with a corresponding alcohol in an inert organic solvent (e. g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.), at a temperature of from 0.degree. C. to 40.degree. C.; and PA1 (3) the method using a condensing agent (e. g., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[(dimethylamino)propyl]carbodiimide (EDC), 2-chloro-1-methypyridinium iodide etc.) may be carried out, for example, by reacting a carboxylic acid with a corresponding alcohol using a condensing agent in the presence or absence of a tertiary amine (e. g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent (e. g., chloroform, methylene chloride, dimethyl formamide, diethyl ether etc.) or without a solvent at a temperature of from 0.degree. C. to 40.degree. C. PA1 R.sup.p is t-butyl or benzyloxycarbonyl, PA1 X.sup.10, X.sup.20 and X.sup.30 each independently, is halogen, PA1 Ms is methaneosulfonic acid, PA1 A.sub.00 is bond, C1-3 alkylene, oxy-(C1-3) alkylene, thio-(C1-3)alkylene, C2-7 alkenylene, C2-7 alkenylene substituted by carboxy or C1-4 alkoxycarbonyl, and the other symbols have the same meaning as hereinbefore described.
and pharmaceutically acceptable salts thereof are useful as LTB.sub.4 antagonist.
3. Comparison with the Related Arts
In the amidinophenyloxy(thio)alkoxy(thio)benzamide compounds represented by EP-518819 as prior art, it can be seen that --X.sub.1a --X.sub.2a --X.sub.3a -- must be --O(or S)-alkylene-O(or S)--, with the proviso that the alkylene may be interrupted by an aromatic group.
It has now been discovered that compounds in which it is essential that the amidinophenyl group is bonded to the phenyl group via an ester or amide group possess useful properties as LTB.sub.4 antagonists and as inhibitors of phospholipase A.sub.2 and/or trypsin.